Project Summary/Abstract Impact: Addiction to cigarettes costs society $138 Billion yearly in health care consequences and lost productivity. It is very hard to quit ? even for smokers who try. Conditions that make it harder for smokers to resist smoking could trigger relapse. One potential culprit is stress - which comes in many forms. But how does stress affect the brain and lead to relapse? Goals: The long-term objective of this multi-modality investigation of the links between acute stress, dopamine (DA) transmission and inhibitory control is to identify targets for therapy that will neutralize the sequela of stress and thereby prevent relapse of drug use. In the current project, we will study smokers who have been abstinent overnight to explore how a stressor may cause them to resume smoking. The immediate objective of the proposal is to test the hypothesis that striatal DA transmission mediates (serves as a link between) effects of biological stress on inhibitory control leading to relapse. Innovation: We will use a biological model of acute stress in humans, a single low dose of endotoxin (lipopolysaccharide(LPS)). For a short period, this stressor reliably elevates various markers of inflammation such as TNF?? as well as sickness symptoms (e.g., muscle pain) and mild mood changes. We were the first to demonstrate with imaging that LPS triggers a cellular immune response in humans ? marked by activated microglia ? as well as alterations in brain metabolism. In addition, our group has introduced and validated a human laboratory model of smoking lapse behavior. We were the first to show that stress hastens reinstatement of cigarette smoking in a controlled lab environment. This project will combine both models as well as functional imaging with PET and fMRI to probe relevant neurochemistry and inhibitory circuitry. Preliminary Findings: Recently, using PET imaging, we showed that acute endotoxin enhances DA transmission in the dorsal striatum. In the human lab, we have found that LPS impairs cognitive control (essential in resisting drug relapse).These novel findings open the door to a mechanistic explanation of the connection between stress and reinstatement of drug use. Approach: We will conduct three main experiments on a cohort of male and female smokers. Experiment #1: Using PET, we will examine the effects of our stress model on DA transmission in smokers. Experiment #2: Using fMRI, we will examine the effects of our stress model on response inhibition. Experiment #3: Using our human lab paradigm, we will measure the effects of our stress model directly on smoking lapse behavior. By combing results from our three experiments, we will determine if (a) stress affects DA signaling and response inhibition in smokers, (b) DA mediates the effect of stress on disinhibition, and (c) if disinhibition predicts smoking lapse behavior.